Motif-Level Graph Learning Enables Interpretable Prediction of Drug-Induced QT Prolongation via Cooperative Substructural Determinants

Drug-induced QT interval prolongation is a critical safety concern in drug development, yet accurate and mechanistically interpretable prediction from chemical structure remains challenging due to the limited substructural resolution of existing approaches. Here, we present a motif-level graph learning framework for interpretable QT risk prediction. In this framework, molecules are decomposed into chemically meaningful motifs, enabling representation at an intermediate structural scale between atoms and predefined structural alerts. Motif features are encoded using a pre-trained chemical language model, and inter-motif relationships are modeled via attention-based graph learning with cross-scale integration. The model is trained and evaluated on two clinically grounded datasets derived from regulatory drug labeling (DIQTA) and real-world pharmacovigilance data (FAERS), achieving strong and consistent predictive performance with robust generalization across data sources. Importantly, motif-level attention reveals that QT liability is associated with the cooperative organization of compact cationic centers and heteroatom-rich, conformationally adaptable scaffolds, rather than isolated functional groups. These patterns are consistent with known determinants of human ether-à-go-go-related (hERG) channel blockade while providing a more structured and chemically specific interpretation beyond conventional structural alerts. Overall, this work establishes a generalizable and interpretable framework for QT risk prediction and highlights motif-level graph learning as an effective strategy for structure-based modeling of adverse drug reactions.